Like many common diseases, autoimmune disorders generally result from a complex mix of pathogenic factors that are environmental and genetic in nature. Among these factors, are likely to be processes that govern the control of immune tolerance which can be broadly separated into central and peripheral tolerance mechanisms. Until recently, however, the role of central tolerance in the pathogenesis of autoimmune disease was unclear. Our laboratory group and others have uncovered a direct link between autoimmunity and central tolerance through the detailed study of the AIRE (for AutolmmuneRegulator) gene. This gene was originally identified through the study of patients with the clinical autoimmune disorder APECED. These patients develop multi-organ autoimmunity, mainly involving the endocrine organs. We have generated AIRE-deficient mice and our previous work with these animals has demonstrated that these animals have a defect in the ability of the thymus to tolerize developing T cells to self-antigens whose expression is controlled by AIRE. This finding has helped establish that central tolerance in the thymus is important in the prevention of autoimmune disease and has provoked us to hypothesize how the central tolerance defect present in these animals interacts with other modifying factors and that this process can be used as a tool to prevent autoimmune disease. This work has important implications for the more detailed understanding of how autoimmune disease(s) occur and how they can be prevented. The model system that is utilized in these studies has a direct link to an existing clinical disorder whose symptoms include autoimmunity to the pancreatic islets, thyroid, adrenal, parathyroid, and liver. The proposed work is designed to learn more about how these important diseases unfold and also how they can potentially be prevented.